Neuropathic pain, also referred to as a chronic pain, is a complex disorder resulting from injury to the nerve, spinal cord or brain. There is evidence that nerve fibers in subjects with neuropathic pain develop abnormal excitability, particularly hyper-excitability. Zimmerman (2001) Eur J Pharmacol 429(1-3):23-37. Although the American Pain Society estimates that nearly 50 million Americans are totally or partially disabled by pain, there are currently very few effective, well-tolerated treatments available. Wetzel et al. (1997) Ann Pharmacother 31(9):1082-3). Indeed, existing therapeutics cause a range of undesirable side effects primarily due to the difficulty in developing small-molecule drugs capable of specifically targeting the receptor/channel of choice.
Studies have shown the existence of primary sensory neurons that can be excited by noxious heat, mechanical damage, intense pressure or irritant chemicals, but not by innocuous stimuli such as warmth or light touch. These nociceptors selectively detect pain-inducing stimuli and appear to be distinct from other sensory mechanisms. This suggests that by suppressing the molecular mechanism of nociception it might be possible to limit the perception of painful stimuli without compromising general sensory awareness.
Transduction of noxious stimuli in nociception is mediated by cellular receptors that typically include non-selective ion channels (e.g., vanilloid receptor, VR1), sodium ion channels (e.g., PN3/NaV1.8), tyrosine receptor kinases (e.g., TrkA), and GPCRs (e.g., bradykinin receptors). The majority of these receptors are expressed only in neuronal cells that are involved in both chronic and acute nociception, making them possible targets for therapeutic intervention aimed at limiting the pain response. Conventional therapeutic approaches typically focus on attempting to identify ligands that function as antagonists for these receptors. However, a major barrier to this approach is the cross-reactivity of receptor antagonists with other receptors of similar structure that are distinct from the pain-related targets.
The study of the molecular mechanisms triggering neuropathic pain has identified several genes that are abnormally expressed in sensory neurons of the Dorsal Root Ganglion (DRG) in models of neuropathic pain, including Vanilloid Receptor 1 (VR1), a non-selective cationic channel responding to thermal, pH and capsacin stimulation (Hudson et al. (2001) Eur J Neurosci 13(11):2105-2114; Walker et al. (2003) J. Pharmacol. Exp Ther 304(1):56-62; Tyrosine kinase A receptor or high-affinity NGF receptor (TRKA), which has been shown to be upregulated in DRG neurons after chronic spinal cord injury (Qiao et al. (2002) J. Comp Neurol. 449(3):217-230); (iii) the sodium channel Nav1.8 (also referred to as PN3 or SCN10A) (Coward et al. (2000) Pain 85(1-2):41-50); and nitric oxide synthase (NOS) (Zimmerman, supra). Lai et al. (2002) Pain 95(1-2):143-152, showed that reduced levels of Nav1.8 correlate with inhibition of neuropathic pain in the rat spinal nerve injury model of chronic pain.
However, the modulation of genes aberrantly expressed in neuropathic pain has not been previously described. Furthermore, the ability to alter expression of these genes may have utility in treating and/or preventing many forms of pain.